So far, as oral therapeutic drugs for diabetes mellitus, biguanide type and sulfonylurea type compounds have been used. However, with biguanide type compounds, lactic acidosis or hypoglycemia is caused and, with sulfonylurea type compounds, serious and prolonged hypoglycemia is caused, and the adverse effect thereof is posing a problem. Therefore, the appearance of new therapeutic agent without such defect is desired.
Moreover, it is known that some of the 2,4-dioxothiazolidine derivatives exhibit hypoglycemic and lipid-lowering effects (Journal of Medicinal Chemistry, vol. 35, P. 1853 (1992) and Japanese Unexamined Patent Publication No. Hei 1-272573), but, in all of these compounds, the position of substitution on middle benzene ring that connects with 2,4-dioxothiazolidine ring and aromatic ring is p-position; the former has oxazole ring for the aromatic ring and the latter has sulfonylamide for the linkage. In addition, both have a carbon chain between middle benzene ring and thiazolidine-2,4-dione ring, structurally different from N-substituted dioxothiazolidylbenzamide derivatives of the present invention.
On the other hand, it has been clear that aldose reductase takes part in the crisis of diabetic complication (Journal of American Medical Association, vol. 246, p. 257 (1981)).
Moreover, it is known that some of the 2,4-dioxothiazolidines exhibit aldose reductase inhibitory activity (Chemical and Pharmaceutical Bulletin, vol. 30, p. 3601 (1982) and Japanese Unexamined Patent Publication No. Hei 5-92960). In the former, the 2,4-dioxothiazolidine ring and the carboxyl group are p-substituted via middle benzene ring and in the latter, the bonding mode to middle benzene ring is acylamino, and the like. Therefore they are sturcturally different from N-substituted dioxothiazolidylbenzamide derivatives of the present invention, and additionally they have only weak hypoglycemic effect.
For the non-insulin dependent diabetes mellitus (NIDDM) that accounts for the majority of diabetic patients, an effective blood sugar-lowering drug with high safety that allows to prevent or cure the complications together with ability for improving insulin resistance and lowering blood sugar is desired.